ABSTRACT Organ fibrosis is an irreversible endpoint of several diseases, leading to organ failure. Systemic sclerosis (SSc) is a prototypic fibrotic disease with fibrosis affecting multiple organs including the lung. Currently the only available therapeutic option for patients with fibrosis is organ transplantation, which is clinically impossible on the scale necessary. The hallmark of fibrosis in multiple organs is the disruption of extracellular matrix (ECM) homeostasis, resulting in accumulation of ECM components and subsequent organ failure. Fibrosis is characterized by upregulation of fibrotic triggers such as connective tissue growth factor (CTGF), increase in the deposition of collagen, fibronectin and other ECM components, enhanced matrix crosslinking due to an increase in levels and activity of lysyl oxidase (LOX) enzyme, and decreased ECM degradation via reduced matrix metalloprotease (MMP) levels and activity. We identified a peptide derived from the carboxy terminal region of human endostatin, named E4, that exerts anti-fibrotic activity in vitro, ex vivo, and in vivo whether administered prior to, concomitantly with, or following a fibrotic trigger such as bleomycin or TGF?. Our recent findings described in the preliminary studies suggest that E4 activates the urokinase pathway via increasing urokinase plasminogen activator (uPA) levels and activity and decreasing those of its inhibitor PAI-1. Mechanistically, E4 engages uPAR and phosphorylated ?-catenin in fibroblast membranes. E4 also decreases Egr-1 levels and increases nuclear levels of Pax6. We propose to 1) determine the role of ?-catenin/E4 and uPAR/E4 interactions in mediating the anti-fibrotic effects of E4, 2) define the role of phosphorylated ?-catenin and its reduced nuclear translocation in mediating the effects of E4, and 3) investigate the role of the transcription factors Egr-1 and Pax6 downstream of E4. The beneficial effect of E4 in multiple pre-clinical models of lung fibrosis emphasizes its relevance to human disease. Our goal is to advance mechanistic knowledge of E4, which will allow for the identification of potential biomarkers and any possible side effects while facilitating further improvement of the peptide as a therapy.